Recent advances and applications of reductive desulfurization

lable at ScienceDirect

Tetrahedron 70 (2014) 8983e9027

Contents lists avai

Tetrahedron

journal homepage: www.elsevier .com/locate/ tet

Tetrahedron report number 1054

Recent advances and applications of reductive desulfurizationin organic synthesis

Jana Rentner, Marko Kljajic, Lisa Offner, Rolf Breinbauer *

Institute of Organic Chemistry, NAWI Graz, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria

a r t i c l e i n f o

Article history:Received 28 March 2014Available online 5 July 2014

Keywords:DesulfurizationRadical reactionRaney-nickelSynthonThiolTotal synthesis

* Corresponding author. E-mail address: breinbaue

http://dx.doi.org/10.1016/j.tet.2014.06.1040040-4020/� 2014 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89832. Mechanistic considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89843. Thiophenes as masked carbon synthons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89864. Saturated S-heterocycles as masked carbon-synthons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89955. Linchpin strategy for the assembly of building blocks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89976. S-heterocycles for deoxygenation of carbonyl groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89997. S-containing functional groups for tuning reactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90038. S-heterocycles for improved selectivity and molecular recognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90069. Acyclic S-compounds for improved selectivity and molecular recognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9009

10. Other applications in organic synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .901511. Reductive desulfurization in peptide chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .902112. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9024

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 902413. Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9024

References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9025Biographical sketch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9027

1. Introduction

While the reductive desulfurization of thiols, thioethers, and S-containing heterocycles is performed on amulti-million ton scale indown-stream oil processing in the production of gasoline, keroseneand Diesel fuel using heterogeneous molybdenum, cobalt,

[email protected] (R. Breinbauer).

tungsten, or nickel sulfide catalysts, the true potential of this re-action in the lab scale total synthesis of natural products, bi-ologically active compounds, or new materials has not beenexploited yet.

In this report we want to give a summary about the opportu-nities offered by reductive desulfurization as a synthetic tool inorganic synthesis and highlight its applications as carbon-synthonsor for tuning the reactivity and selectivity of reactions. There havebeen comprehensive reviews about the desulfurization of thio

Delta:1_O

Delta:1_S

Delta:1_given name

Delta:1_surname

mailto:[email protected]

http://crossmark.crossref.org/dialog/?doi=10.1016/j.tet.2014.06.104&domain=pdf

www.sciencedirect.com/science/journal/00404020

http://www.elsevier.com/locate/tet

http://dx.doi.org/10.1016/j.tet.2014.06.104



J. Rentner et al. / Tetrahedron 70 (2014) 8983e90278984

compounds with Raney-nickel by van Tamelen1 and Hauptmann2

from 1962 and a book chapter by Gol’dfarb3 from 1986. This re-view article builds on these earlier review articles to describe thecurrent state of this subject and complements review articles aboutreductive desulfonylation,4,5 which will not be covered in this re-port, as this article focuses on non-oxidized sulfur species, such asthiols, thioethers, and thiophenes. This review also will not discussthe metal-catalyzed C(sp2)-SR cleavage as it has found numerousapplications for the removal of RS-substituents as a strategictransformation in heterocyclic chemistry and can be reliably ac-complished by a variety of methods.6e10 We have structured thematerial according to the fields of application, using the followingcategories: 1) thiophenes and saturated S-heterocycles as carbonfragments, 2) assembly of organic frameworks using the linchpinstrategy, 3) deoxygenation of carbonyl groups via thioketalization,4) increasing the reactivity of reactions by tuning the electronicproperties of reagents, 5) increasing the selectivity of reactions byconformational restriction, and 6) as functional handles in peptidechemistry (Scheme 1). Naturally, certain applications would fit intomore than one category, sowe arbitrarily classified such applicationinto a single category to avoid overlap.

The first examples of desulfurization of thioethers (e.g., 1),11 S-containing amino acids (e.g., 2e3),11,12 or biotin methyl ester(4)13e15 have been reported by Mozingo et al. from Merck & Co in

Scheme 1. Key transformation us

the 1940’s establishing Raney-Ni as a reagent for reductive de-sulfurization. Soon the desulfurization of thioketals (e.g., 5)16 andthiophenes (e.g., 6)17,18 was realized by other groups (Scheme 2).

2. Mechanistic considerations

As listed in Scheme 2 Raney-Ni has historically been the firstreagent, which enabled the desulfurization of thiophenes and thi-oethers and is until today the reagent of choice for these trans-formations. Activated Raney-Ni can be categorized into sevendifferent generations W-1 up to W-7, all types differing in reactiontime for Raney-Ni synthesis and workup conditions.19e23 MurrayRaney reported the first Raney-Ni catalyst in 1927 without immo-bilization of themetal on a surface.24W-2 toW-7 type Raney-nickelcatalysts are advancements of this first catalyst and show in generalincreased reactivity mainly to varying functional groups. In parallel,its stability decreases. These catalyst generations must be synthe-sized shortly before use and cannot be stored over a longer period.Another very important fact is their extremely high inflammabilityincreasing with the catalyst generation. All Raney-nickel catalystsincorporate emerging hydrogen during its synthesis from nickel-ealuminium alloy under basic conditions. Due to the highly pyro-phoric properties of all Raney-nickel catalysts they are only stored

ing reductive desulfurization.

Scheme 2. Historically first examples of reductive desulfurizations.

J. Rentner et al. / Tetrahedron 70 (2014) 8983e9027 8985

and handled as suspension. Stating the exact amount of catalyst fora reaction is therefore impossible.

Because of its complex nature as a skeletal catalyst resultingfrom alkaline leaching of a NiAl-alloy the investigation of the re-actionmechanism is complicated by various Ni crystal faces and thesurface decoration with adsorbed hydrogen or oxygen species.Therefore, our current knowledge about the mechanism of de-sulfurization on Ni surfaces is based on studies on model systems,such as X-ray photoelectron spectroscopy studies (XPS) under ul-trahigh vacuum (UHV) conditions of the chemisorption of

Scheme 3. Plausible mechanism for desulfu

thiophene25 and thioether26 on Raney-Ni and thiophene onNi(111),27 X-ray absorption spectroscopy of dibenzothiophene onNi/ZnO28 and more recently of computational DFT calculations ofthiophene adsorption and dissociation on various Ni crystal faces.29

From these studies a consensual mechanistic proposal can be de-lineated (Scheme 3). Adsorption of thiophene on the Ni surfaceresults in the geometric distortion of the adsorbed molecule andthe loss of aromaticity of the thiophene ring. Donation from thesulfur lone pair to the Ni-atoms is paralleled by back donation fromNi d-orbitals to the p-electrons of the carbon framework.29

rization of thiophenes on Ni surfaces.


Depending on the crystal face several mechanistic pathways arediscussed for the following CeS dissociation step, which very likelyinvolves a metallocycle intermediate. The CeS dissociation step hasa surprisingly low activation barrier. Under UHV conditions CeScleavage occurs on Raney-Ni for thiophene25 and dipropylsulfide26

at around 170 K. The hydrogenation of the olefins of the formedolefin species is believed to have a higher activation barrier. Whileit is well known that saturated S-heterocycles and thioethers aremore reactive than thiophene in the desulfurization reaction withRaney-Ni and industrial HDS catalysts, such as Mo and Co, currentevidence suggests that the S from thiophene is removed directlywithout prior hydrogenation as this process would be energeticallyunfavourable.30

While the spectroscopic proof of a postulated metallathiacycleon a Ni surface is still awaited, there are several homogeneousmetal complexes known, which make these species very plausi-ble.31 Jones et al. have for example, shown that [(dippe)NiH]2 (I)readily reacts with thiophene to form the nickelthiacycle II, whichhas been characterized by X-ray crystallography (Scheme 4).32

Scheme 4. Reaction of a nickelhydride precursor with thiophene.

In a second line of mechanistic reasoning Eisch et al. have pos-tulated that homogeneous hydrideeNi(0) complexes induce CeScleavage via single electron transfer (SET),33 which parallels similar

Scheme 5. Reductive desulfurizatio

Scheme 6. Synthesis of

transformations for thioether cleavage enabled by lithium/ethyl-amine or LiDBB.

3. Thiophenes as masked carbon synthons

Building on the first historic precedence described above inScheme 2 Gol’dfarb et al. have extensively studied in a series ofpublications in the 1960’s (mostly written in Russian) the use ofthiophene as a C4-building block. In Scheme 5 an elegant syntheticsequence is depicted, in which thiophenes are transformed to ali-phatic amino acids. For example, thiophene 13 can be convertedinto a-aminoenanthic acid 14 in 53% yield. 5-Acetamidothiophene-2-carboxylic acid (15) was desulfurized into d-acetamidovalericacid (16) in formidable 96% yield, whereas bicyclic derivative 17was transformed into ε-ethyl-ε-caprolactam (18) in 82% yield(Scheme 5).34

Gol’dfarb’s strategy was applied by Mandolini et al. in an earlysynthesis of (rac)-muscone (21) (Scheme 6).35 The macrocycle wasformed via an intramolecular FriedeleCrafts acylation ofthiophene-carboxylic acid 19 to form 14-membered structure 20,which upon reductive desulfurization expanded to 15-ring ketonemuscone (21).

Stetter et al. could show that cyanide ions catalyze the additionof aromatic aldehydes across Michael-acceptors. An elegant way toformally extend the scope of this reaction to aliphatic aldehydes isthe use of thiophene aldehydes, which offer the advantage of beingnon-enolizable, but after 1,4-addition and reductive desulfurizationgive access to g-ketocarboxylic acids. In Scheme 7 the conversion ofdialdehyde 22 into diketocarboxylic acid 25 illustrates this strategy,in which the solvent ethylmethylketone (EMK) prevents reductionof the keto group.36

Gronowitz et al. took advantage of the fruitful combination offlexible thiophene substitution reactions with a subsequent re-ductive desulfurization with Raney-Ni to produce a series of

n of thiophenes by Gol’dfarb.

(rac)-muscone (21).

Scheme 7. Stetter reaction with thiophene aldehydes.


branched fatty acids. In Scheme 8 this approach is demonstrated forthe synthesis of 4-ethylhexanoic acid (30). Metallation of 3-ethyl-2-methylthiophene (28) and electrophilic quench with dry ice pro-duced thiophene carboxylic acid 29, which upon reductive de-sulfurization with Raney-Ni generated branched fatty acid 30 in

Scheme 8. Synthesis of branched fatty acids.

77% yield.37 Branched fatty acids could also be synthesized usinga similar strategy.38

Analogous strategies have been pursued for the synthesis of ir-regular isoprenoid and extended phytane carbon skeletons.39

Scheme 9. Synthesis of a select

As a tool compound for mechanistic enzymatic investigationsBoland et al. prepared the partially deuterated analogue of palmiticacid 35 as a mechanistic probe.40 2,2-Bithienyl (31) functioned asa C8-building block, which after lithiation is reacted with enzy-matically prepared chiral building block 32 to furnish 33, which istransformed into ester 34 via a lithiation/electrophilic quench se-quence. Desulfurization of 34 was accomplished with nickel borideprepared from NiCl2 and NaBD4 in deuterated MeOH/THF to war-rant a high degree of isotopic labelling. Subsequent saponificationof the ester delivered the desired deuterated palmitic acid 35(Scheme 9).

Similarly, perdeuterated heptanoic acid ester 38 was preparedby the dehalogenation and desulfurization of methyl 3-chloro-5,6-dibromothieno[3,2-b]thiophene-2-carboxylate (37) with Raney-Niin 10% NaOD/D2O (Scheme 10).41

The multifold use of thiophene as C4-building block has alsobeen shown by Cantor et al. in the preparation of a series of poly-hydroxyalkanes 42 as anaesthetics by using thiophene as a tem-plate to position the carbinol groups between C4-tethers(Scheme 11).42

For the synthesis of long chain alkane derivatives the sequenceof FriedeleCrafts acylation of thiophenes, followed by Wolf-feKishner-reduction and reductive desulfurization has proven tobe a very useful method, which only recently has seen competitionby olefin cross metathesis. Knapp Jr. et al. used the desulfurizationof such a thiophene linker in the synthesis of the myocardial im-aging agent 46 (Scheme 12).43

Similarly, Sargent et al. produced the u-phenylalkylcatechol 50,which occurs in the Burmese lac tree Melanorrhoea usitata(Scheme 13).44

ively deuterated fatty acid.

Scheme 10. Synthesis of perdeuterated heptanoic acid (38).

Scheme 11. Cantor’s synthesis of anaesthetics 42.

Scheme 12. Synthesis of a myocardial imaging agent.


Noe et al. showed that alkoxy-substituted thiophenes can bepartially reduced to the corresponding enolethers, which uponacidic hydrolysis can be transformed to the corresponding ketones,such as 52 (Scheme 14). Based on this rationale they succeeded inthe racemic synthesis of the antiaggression pheromone 54 of thewasp (Paravespula vulgaris) by reductive desulfurization of 53.45

Niphatesine C (60) is an alkaloid isolated from a marine spongefound near Okinawa Island, which shows moderate antimicrobialactivity. In the total synthesis of 60 Bracher set the carbon skeleton

by reaction of acid chloride 55 with enantiomerically pure thio-phene 56. WolffeKishner-reduction and reductive desulfurizationwith Raney-Ni produced alkylpyridine 59, which through func-tional group transformation furnished niphatesine C (60)(Scheme 15).46

In their synthesis of dimethoxy[8]paracyclophane (65) Tashiroet al. first assembled the dithia[3.3]paracyclothiophenophane 63 byreaction of bisbenzylthiol 62 with bis(chloromethyl)thiophene 61.Photolytic desulfurization of the thioether groups in 63 in neat

Scheme 13. Synthesis of u-phenylalkylcatechol 50.

Scheme 14. Preparation of enolethers and their conversion into pheromones.

Scheme 15. Synthesis of niphatesine C (60).



P(OMe)3 as solvent produced thienophenophane 64, which aftertreatment with Raney-Ni was debrominated and desulfurized to 65(Scheme 16).47

Sone et al. prepared a series of crown ethers 66 containingthiophene units and tested their binding affinity against alkalimetal cations.48 Reductive desulfurization with Raney-Ni afforded

Scheme 16. Synthesis of dimethoxy[8]paracyclophane (65).

the corresponding crown ethers 67 having two adjacent sub-stituents as a cis/trans mixture of isomers (Scheme 17).

For the synthesis of the largest so far known bicyclo[n.n.n]alkane the group of Oda has first produced trithienylmethano-

Scheme 17. Preparation of crown ethers 67.

phane 68 by McMurry-coupling of tris(5-formyl-2-thienyl)methane. Subsequent reductive desulfurization of 68 with Raney-Ni produced bicyclo[10.10.10]dotriacontane 69 in 82% yield(Scheme 18).49

Scheme 18. Synthesis of bicyclo

The synthesis of meso-trialkyl-substituted subporphyrins 71could not be achieved by the condensation of pyridine-tri-N-pyr-rolyl-borane with aliphatic aldehydes despite considerable exper-imentation, while this protocol has proven useful to producesubporphyrins with aromatic aldehydes. Therefore, Osuka et al.synthesized the meso-trithienyl-subporphyrins 70aec in 0.9e3.7%

yields. Reductive desulfurization with Raney-Ni converted thethiophenes into alkyl groups, but also led to overreduction prod-ucts, which could be easily oxidized back with chloranil to furnishthe trialkyl-subporphyrins 71aec (Scheme 19).50

The desulfurization of thiophenes has also been used in thesynthesis of highly substituted 1,2-azaborines.51,52

Jones et al. presented a short stereoselective synthesis of es-tradiol and its 6,6-dimethyl analogue 75 starting from readily ac-cessible 1,11-epithiosteroids.53 72 was desulfurized with Raney-Ni,which established the natural 9a-H-configuration but was accom-panied with reduction of the benzylic carbonyl group. Reoxidationwith BaMnO4 set the stage for a BaeyereVilliger-oxidation to pro-duce 74. Twofold reductive ester cleavage delivered 6,6-dimethylestradiol (75) (19% overall yield from 2-methylcylopentenone) (Scheme 20).

Jacobi has recognized that the reductive desulfurization of 3-methylthiophenes produces an isoprenyl-unit and applied this in-sight in a synthesis of the terpenoid natural product 7a-eremo-philane (79) (Scheme 21).54 Starting from thiazole A anintramolecular DielseAlder-reaction between thiazole and alkynemoieties followed by a retro-[4þ2]-reaction under the release of

[10.10.10]dotriacontane 69.

Scheme 19. Synthesis of subporphyrins 71aec.

Scheme 20. Synthesis of the estradiol analogue 75.

Scheme 21. Synthesis of the terpenoid natural product 7a-eremophilane (79).



HCN produced substituted thiophene 77, which was converted tosesquiterpene 78 by desulfurization with Raney-Ni. Removal of theCO-group via a reduction followed by a BartoneMcCombie-de-oxygenation of the resulting alcohol produced 79.

The group of Daich has developed a synthetic sequence of bi-ologically interesting substituted indolizidinols based on reductivedesulfurization of thiophenes (Scheme 22).55 Starting from thio-

Scheme 22. Synthesis of ethyl-indolizidinol 83.

phene-2-carboxaldehyde (80) and L-glutamic acid intermediate 81was produced in 55% yield over three steps. Reductive de-sulfurization of 81 occurred in 90% yield to produce a mixture offour possible diastereomers (68:12:10:10), fromwhich 82 could be

Scheme 23. Diastereoselectivity in

crystallized in 52% isolated yield. Interestingly, the reductive de-sulfurization was accompanied by reduction of the carbonyl group,which is in contrast to the general functional group tolerance of thistransformation for other substrates. Reduction of 82 with LiAlH4produced ethyl-indolizidinol 83.

When using benzo[b]thiophenes the corresponding phenyl-indolizidines were produced.56,57 In the course of these studies the

diastereoselectivity of the reduction process was carefully studied,revealing that in general hydrogen is delivered from the stericallymore accessible face, but that polar substituents lead to secondaryeffects (Scheme 23).56

the reaction benzothiophenes.


More recently, Honda et al. have presented a spectacular totalsynthesis of the natural cholestane diglycoside OSW-1 (95), whichexhibited extremely high cytotoxic activity against human malig-nant cancer cells. The thiophene moiety was introduced by alkyl-ation of alcohol 90 with 91. Base-induced Wittig-rearrangementconverted 92 into alcohol 93, which was then elaborated into ad-vanced intermediate 94. Despite the structural and functionalcomplexity of 94, featuring free hydroxyl groups, ester groups andan isolated olefin, the reductive desulfurization with deactivatedRaney-Ni W2 and hydrogen at rt occurred in very good 79% yield todeliver OSW-1 (95) (Scheme 24).58

Scheme 24. Synthesis of cholestane diglycoside OSW-1 (95).

Krishna et al. used thiophenes for the production of C-glyco-sides.59 2-Lithiothiophene adds to lactol 96, which underMitsunobu-conditions furnishes C-aryl glycoside 97. Reductivedesulfurization produces C-butyl glycoside 98 (Scheme 25).

Kim et al. have developed a versatile method for the productionof 2-substituted 3-alkylamino-5-arylthiophenes by reaction of

Scheme 25. Synthesis

thioaroylketene S,N-acetal 99 with silylenolethers. Reaction of 99with 100 produced ring enlarged thienolactam 101, which upondesulfurization delivers 102 (Scheme 26).60 The authors stated thatdesulfurization with Raney-Ni produced partially hydrogenatedproduct containing olefin, therefore a second hydrogenation withPtO2 was necessary to produce the alkyl-substituted product 102.However, hydrogenation with PtO2 alone did not convert 101,confirming the observation that Ni is necessary to induce thedesulfurization.

Viner et al. from Syngenta prepared the nanomolar acting ace-tylcholinesterase inhibitors 105aeb, which have been designed as

chimeras of tacrine and 3-(N,N,N-trimethylammonio)tri-fluoroacetophenone.61 Thiophene 103 was lithiated with LDA andreacted with the trifluoroacetic Weinreb amide forming 104. Re-ductive desulfurization produced the aliphatic trifluoromethylketones 105aeb as the corresponding hydrates due to the stabi-lizing effect of the trifluoromethyl group. The Raney-Ni reaction led

of C-glycosides.

Scheme 26. Reductive desulfurization of a thienolactam.


to partial dechlorination of the arene leading to a product mixture,which could be separated by flash chromatography (Scheme 27).

Fang et al. have developed a method, in which methyl thio-phene-2-carboxylates or methyl-3-(thien-2-yl)acrylate (107) aretransformed with SmI2 into carbanion equivalents, which can react

Scheme 27. Synthesis of acetylcholinesterase inhibitors.

with electrophiles, such as 106 to produce CeC-coupling products,such as 108. Reductive desulfurization of the dihydrothiopheneintermediates with Raney-Ni produces aliphatic hydroxy-alkanoicacid esters, as has been exemplified for the spore germination in-hibitor 109 (Scheme 28).62

Scheme 28. Synthesis of aliphatic hydroxyl

For chemical proteomics purposes to identify the protein targetsof small molecule drugs, the small molecule needs to be attached toa solid support. As very often the functional groups available at thedrug molecule prove essential for the biological activity, Rentnerand Breinbauer have developed a labelling strategy for drug-like

molecules taking advantage of the less relevant but abundant CH-arene bonds of the small molecule via Pd(II)-catalyzed dehydro-genative coupling. As the methodology for Csp2eCsp3 coupling isnot satisfyingly developed yet, they used a two-step sequence, inwhich first a Csp2eCsp2 coupling with functionalized thiophenes

-alkanoic esters via thienyl carbanions.


was performed.63 For example, modified caffeine 110 was firstreacted via dehydrogenative cross-couplingwith various thiophenederivatives 111 followed by subsequent reductive desulfurizationwith Raney-Ni producing the desired flexible alkyl chain(Scheme 29). A benefit of this hydrodesulfurization is the simul-taneous cleavage of appropriate protecting groups. The obtainedalkylated caffeine 113 can finally be attached directly to a solidsupport or markers for further studies (Table 1).

Scheme 29. Labelling of drug-like molecules via dehydrogenative coupling of functionalized thiophenes.

Table 1Screening of thiophenes in drug tethering

Entry FG1 of 111 Yield FG2 of 113

112 113

1 CH3 98% 85% CH3

2 CH2NHBoc 99%a 83% CH2NHBoc3 CH2NHCbz 97%b 40% CH2NH2

4 CH2OH 63% 40% CH2OH5 CH2OBn 89% 99% CH2OH

a Addition of 0.2 equiv CuCl.b Addition of 0.1 equiv 1,10-phenanthroline.

In conclusion, thiophene is a very functional C4-building block,which requires the use of Raney-Ni as a desulfurization agent, as Nihas proven to be instrumental to break the SeC bond. The func-tional group tolerance is rather high, but olefins and halogens areusually also subjected to hydrogenation resp. hydrogenolysis, al-though exceptions are known and have been described in thischapter. Nickel boride (in situ prepared from NiCl2, NaBH4) hasbeen demonstrated to be milder than Raney-Ni.

Scheme 30. Control of olefin geometry in the stere

4. Saturated S-heterocycles as masked carbon-synthons

While thiophenes can be excellently decoratedwith substituentstaking advantage of the full repertoire of arene substitution andfunctionalization reactions their application is limited as a mere C4-building block. Using various partially saturated or completely sat-urated S-heterocycles overcomes this limitation and expands thescope of this reaction strategy to other Cn-building blocks.

Palumbo et al. reported an approach, in which 5,6-dihydro-1,4-dithiins were used as C2-building blocks, which upon reductivedesulfurization produced not the expected alkane but alkeneproduct. Coupling of lithiated dithiin 114 with chiral aldehydes115e117 and subsequent reduction enabled access to poly-hydroxylated compounds. The intermediates 118were desulfurizedaccording to their previous report on sulfur removal from dithiins(Scheme 30).64 While reductive desulfurization of 118 with Raney-Ni produced the (Z)-olefin 119 the desulfurization of 118a withLiAlH4/Ti(OiPr)4/quinoline (16:8:0.15) in ethanol at 50 �C led to 72%119a as an exclusive (E)-olefin isomer.65

In subsequent publications from the Palumbo group the cou-pling of phenylic and O-allylic dithiins was successfully tested withseveral other electrophiles.66,67 Iodomethane, benzylbromide, ep-oxides, aldehydes, and even D-galactono-d-lactones were efficientlycoupled. Reductions were always performed with optimizedRaney-Ni conditions mostly in THF. The remaining double bondafter desulfurization offers opportunities for further de-rivatizations. For example, this double bond served for the totalsynthesis of several modified sugars like alloses, L-(and D-) hexosesand L-hexopyranose analogues.68e71 A very interesting example ofthis strategy is highlighted in Scheme 31 with their synthesis of 1-

oselective reductive desulfurization of dithiins.

Scheme 31. Dithiins as a reagent for iminosugar synthesis.


deoxy-L-iminosugars starting from non-carbohydrate materialsdithiin 120 and Garner aldehyde 121.72 Central intermediate 123could either be desulfurized to unsaturated piperidine 124 undercontrolled conditions with Raney-Ni in 76% yield, whereas harsherconditions in THF led to complete reduction of the olefin to producesaturated product 125 in 83% yield.

Sulfur heterocycles can also be used to serve as a C1-buildingblock. Cozzi et al. described a new approach to a-alkylated alde-hydes by stereoselective organocatalysis and subsequent reductivedesulfurization (Scheme 32).73 1,3-Benzodithiolylium tetra-

Scheme 32. Benzodithiolylium tetrafluoroborate (127) as an alkylating agent in enantioselective organocatalysis.

Scheme 33. Preparation of chiral alcohols 132.

fluoroborate (127) was used as an alkylating agent. The optimizedreaction conditions were found to be the MacMillan catalyst andbenzoic acid in the presence of a 1:1mixture of H2O and CH3CN and

the inorganic base NaH2PO4. Reduction with NaBH4 affords thebenzodithiol derivative 128, which yields the alcohol 129 after re-ductive desulfurization with Raney-Ni. Cozzi et al. published thismethylation strategy with a variety of aldehydes, where they re-ceived high ee-values of 92e97%.

Benzodithiol derivative 128a can be further transformed afterbenzyl-protection by subsequent lithiation and treatment with anelectrophile (MeI or BnBr) (Scheme 33).73 After final reductivedesulfurization with Raney-Ni the differently substituted alcohols132 were produced.

By using 1,3-benzodithiolylium tetrafluoroborate 127 with al-dehydes in the presence of the amine catalyst 134 and (�)-CSACozzi et al. formed quaternary stereocentres under mild reaction


conditions and without using transition metals.74 The enaminemediated alkylation of a-substituted aldehydes was complementedby reduction and removal of the benzene-1,2-dithiol activatinggroup with Raney-Ni. This synthetic strategy was demonstrated inthe synthesis of chiral alcohol 138 starting from 2-phenylpropanal(A133). It should be noted that Raney-Ni reduction did not effi-ciently deprotect the benzyl group, which made a second reductionstep with Pd/C necessary (Scheme 34).

Scheme 34. Organocatalytic synthesis of alcohols with quaternary stereogenic centres.

Analogously, Cozzi et al. functionalized directly a variety ofaryltetrafluoroborate salts via 1,3-benzodithiolylium tetra-fluoroborate reaction.75 By using 2.5 equiv of the benzodithiolyliumsalt 127,140 is formed via hydride shift.140 is stable in the presenceof air and can be easily isolated and purified. NaBH4 reduction af-fords the neutral 141 in high yields. These benzodithiolylium de-rivatives can either be desulfurized directly or furtherfunctionalized with an electrophile followed by reductive de-sulfurization. Cozzi et al. demonstrated this exemplarily withphenyltetrafluoroborate 139 producing ester 143 (Scheme 35).

Scheme 35. Benzoditholylium salt (127) in the coupling with aryl-nucleophiles.

5. Linchpin strategy for the assembly of building blocks

When the concept of umpolung was first introduced by Wittigin the 1920’s describing the inversion of charge, it was not imme-diately accepted by the scientific community. About 50 years later

Corey and Seebach successfully reintroduced the term, definingumpolung as the inversion of polarity and hence of reactivity ofa functional group by chemical modification. Umpolung-basedstrategies are of great significance for organic synthesis. Espe-cially the synthetic potential of 1,3-dithiane linchpins serving assulfur-stabilized acyl and alkyl anion synthons has been recognizedleading to their application in the synthesis of complex natural andunnatural products.76

These nucleophilic acylating and alkylating agents are preparedby Lewis or Brønsted acid catalyzed conversion of aldehyde 144with 1,3-propanedithiol and deprotonation of dithiane 145 withalkyllithium yielding 2-lithio-1,3-dithiane (146). After reactionwith an electrophile the dithioketal moiety may be hydrolysed togive ketone 148 or it could be converted by reductive de-sulfurization yielding alkane 149 (Scheme 36).77

The ability to react with a wide range of electrophiles includingalkyl halides, aldehydes and ketones, epoxides and aziridines, acylhalides and a,b-unsaturated carbonyl compounds makes 1,3-

dithianes a valuable tool for complex molecule synthesis(Scheme 37).76

Other reports reviewing the application of 1,3-dithianes in thetotal syntheses of natural products cover the literature until2004.76,77 Therefore, we will focus on the review of some of

Scheme 36. Opportunities in 1,3-dithiane chemistry.

Scheme 37. Diversity generation through linchpin strategy.


the most recent reports on the subject of dithiane basedchemistry.

Smith et al. achieved the total synthesis of the alkaloid(�)-indolizidine 223AB (155) by one-pot three-component linch-pin coupling of silyl 1,3-dithiane 150 with epoxide 151 anddafterBrook rearrangementdwith N-toluenesulfonyl aziridine 152. Lith-iation of dithiane 150 followed by the addition of epoxide 151 andaziridine 152 in HMPA yielded 153, the carbon backbone of(�)-indolizidine 223AB. Deprotection and one-pot activation of thealcohols and deprotection of the amine gave the double cyclizationproduct 154, which was transformed to the desired (�)-indolizi-dine 223AB (155) by reductive desulfurization with Raney-Ni(Scheme 38). This synthetic strategy exploits the potential of the1,3-dithiane as a linchpin in carbon backbone formation and as anauxiliary accelerating the cyclization reaction.

Due to the flexibility of the available epoxide and the aziridinereagents, the three-component linchpin coupling is a promisingstrategy for the total syntheses of other indolizidine, quinolizidineand quinolizine alkaloids.78,79

The synthesis of carbafuranoses and their conversion to thecarbanucleosides 20,30-dideoxycarbathymidine (160) and 20,30-

dideoxy-60-hydroxycarbauridine via convergent or linear nucleo-base introduction was achieved by the group of Linclau. Since theirstrategy does not start from natural sugars but from arabitoldwithboth enantiomers equally availabledD- and L-carbanucleosides areaccessible. The synthesis of carbafuranose 157 was accomplishedvia a Brook rearrangement mediated stereoselective linchpin cy-clization reaction of silyl 1,3-dithiane 150 and chiral epoxide 156.Having the correct relative stereochemistry (anti-configuration ofthe 10-OTBS and the 40-hydroxymethyl group) the dithioketal groupof carbafuranose 157 was removed by desulfurization with Raney-Ni. After acylation of the hydroxymethyl group and desilylation ofthe secondary hydroxy group, 158 was converted to the desiredcarbanucleoside 160 via a Mitsunobu reaction with nucleobase 159as nucleophile (Scheme 39).80,81

By 1,3-dithiane bi-alkylation Dai et al. accomplished the totalsynthesis of two diastereomeric butenolide alcohols, (4S,10S,11S)-and (4S,10R,11R)-4,11-dihydroxy-10-methyldodec-2-en-1,4-olide(168) (Scheme 40). The syn-aldol subunit was synthesized bya syn-selective aldol reaction and converted to chiral iodide 162.Together with the iodinated chiral building block 164,162was usedin the three-component linchpin coupling with 1,3-dithiane 161.Reductive desulfurization of the coupling product 165 with Raney-Ni yielded 166 in excellent 93% yield. Selective deprotection of theprimary alcohol and its oxidation gave the aldehyde, which wastransformed to the alkene in a Wittig olefination. The secondaryalcohol was deprotected yielding the allyl alcohol, which was ac-ylated to give the acrylate 167. The desired butenolide 168 wasachieved by a ring-closing metathesis reaction applying a Grubbssecond generation catalyst and the removal of the THP ether. Thelinchpin coupling constitutes a flexible strategy for the synthesis ofthe other diastereomers.82

Similar to the linchpin strategy is the dilithiomethane equiva-lent 170 introduced by Cohen and applied in their synthesis of(rac)-hirsutene (177).83,84 2-Methyl-2-cyclopentenone (169) reac-ted with lithiated species 170 in a 1,4-addition to form 171, whichwas thiolithiated in situ with s-BuLi to furnish reagent 172, againundergoing 1,4-addition with 5,5-dimethylcyclopentenone (173).By addition with FeCl3 the enolates were coupled oxidatively totriquinane 175 in excellent diastereoselectivity, which is rational-ized by reversible bond cleavage and bond formation of the in-termediate radical species. Desulfurization with Raney-Niproduced 177, which was elaborated to hirsutene (177)(Scheme 41).

Scheme 38. Synthesis of (�)-indolizidine 223AB (155).

Scheme 39. Synthesis of carbanucleoside 20 ,30-dideoxycarbathymidine (160).


In conclusion, the use of geminal thioacetals offers a variable C1-synthon, which has found widespread application for the assemblyof carbon framework. In the case of 1,3-dithiane reductive de-sulfurization results in a CH2-unit, which nicely complements thetypical oxidative or hydrolytic workup delivering a C]O functionalgroup.

6. S-heterocycles for deoxygenation of carbonyl groups

The deoxygenation of keto groups to methylene units canbe accomplished by a variety of methods, including the

WolffeKishner-reduction, the Clemmensen-reduction, etc. Asmany of these methods involve quite harsh reaction conditionsrequiring strong bases, acids or elevated temperature, a two-stepprocedure, in which the keto group is first transformed into a thi-oketal and in a second step desulfurized with Raney-Ni has becomevery popular in the synthesis of natural products. In the literaturethis transformation is sometimes named as the ‘Wolf-romeKarabinos-method’ after the inventors of this protocol.16

Sometimes also the name ‘Mozingo-reaction’ can be found, whichin our opinion is better used as a general term for reductive de-sulfurization of thioether bonds.

Scheme 40. Synthesis of butenolide 168 via linchpin strategy.

Scheme 41. Synthesis of (rac)-hirsutene (177).


In their synthesis of the triquinane sesquiterpenoid methylcantabrenonate 181, Piers et al. converted the more reactive alde-hyde group in intermediate 178 into thioacetal 179, while leavingthe keto group unreacted. Deoxygenation with Raney-Ni in-troduced the methyl substituent in 180, which was transformedultimately into the desired target structure 181 (Scheme 42).85

Scheme 42. Synthesis of synthesis of the triquinane sesquiterpenoid methyl cantabrenonate 181.

Fukumoto et al. reduced thioketal 182 with Raney-Ni to formlactone 183, which was further elaborated to D9(12)-capnellene 184(Scheme 43).86,87

Maguire et al. applied this two-step sequence in their synthesisof the daucane sesquiterpene analogue 187.88 Ketone 185 wastransformed into the thioketal 186, which was desulfurized withRaney-Ni to furnish 187 letting the olefinmoiety intact (Scheme 44).

Kuwahara et al. used the transformation of a formyl group intoa methyl group for their synthesis of the olfactory compound Lasiol

(190) (Scheme 45).89 Lactol 188 was converted into a thioketal,which was converted into ethoxyethyl (EE) ether 189more suitablefor the subsequent desulfurization. Reductive cleavage of the

Scheme 43. Synthesis of D9(12)-capnellene 184.

Scheme 44. Synthesis of daucane sesquiterpene analogue 187.

Scheme 45. Synthesis of the olfactory compound Lasiol (190).


thioketal with Li/EtNH2 and deprotection of the EE ether produced190 (Scheme 45).

Wakamatsu et al. used the deoxygenation of carbonyl groups viathioketalization in their synthesis of decan-9-olide (193)da naturalproduct, which first has been isolated from the metasternal glandsecretion of Phoracantha synonyma (Scheme 46).90

Scheme 46. Synthesis of decan-9-olide (193).

Similarly Ayer et al. transformed 194 into (rac)-geosmin (196)(Scheme 47).91

Fukumoto et al. presented a fascinating synthesis of the des-A B-aromatic steroid 200.92 Thermolysis of 197 resulted in ortho-qui-nodimethane 198, followed by intramolecular DielseAlder-


reactionwith the vinylsulfidemoiety to assemble the structure 199,which upon desulfurization of the phenylthio group and the tran-sition state stabilizing thioketal produced target compound 200(Scheme 48).

For their research on biomimetic polyene cyclizations the groupof Zeelen aimed at the synthesis of DL-19-nor-4-pregnen-20-one

(203).93 This reference compound was synthesized by first form-ing the thioketal with the more reactive a,b-unsaturated ketone in201 to 202 with subsequent reduction via Li/NH3 (Scheme 49).

The total synthesis of (�)-stypoldione (206) was achieved by thegroup of K. Mori. This cyto- and ichthyotoxic diterpenic metabolite

(rac)-geosmin (196).

Scheme 48. Synthesis of des-A B-aromatic steroid 200.

Scheme 49. Synthesis of DL-19-nor-4-pregnen-20-one (203).


of Lamouroux papenfus was synthesized in 17 steps encompassinga critical deoxygenation of a keto-group in one of the last steps ofthe synthetic sequence.94 Reduction of the C-4 carbonyl was

Scheme 50. Total synthesis o

enabled via thioketalization of 204 with ethane-1,2-dithiol andboron trifluoride followed by subsequent hydrogenolysis withRaney-Ni to produce 205 in 67% (Scheme 50).

f (�)-stypoldione (206).


Pedro et al. managed a synthesis of herbolide I, in which a two-step deoxygenation through the thioketal intermediate 208 wasused. Desulfurizationwas achieved with Raney-Ni in very good 89%yield without overreduction of the olefin moiety (Scheme 51).95

The final sesquiterpene lactones (210, 211) led to the conclusionthat for herbolide I an erroneous structure has been published ina preceding paper.96

Scheme 51. Selective desulfurization in the presence of an olefin.

The deoxygenation of ketones via desulfurization of thioketalshas been especially popular for total syntheses of sesquiterpenes.Srikrishna et al. elegantly used this approach for the regioselectivethioketalization of dione 213 towards (þ)-seychellene (216). Themore sterically demanding ketone remained untouched. Sub-sequent desulfurization of 214 with Raney-Ni led quantitatively tobis-norseychellenone (215). Similar results were achieved in thesame work towards ent-seychellene (þ)-(216) (Scheme 52).97

Scheme 52. Total synthesis of (þ)-seychellene (216).

Fadel et al. presented a synthesis of (þ)-b-cuparenone (220)using chiral precursor 217 as a central intermediate, whose qua-ternary stereogenic centre has been prepared by specific hydrolysisof an a,a-disubstituted malonic ester substrate with PLE. Removal

of the keto group was accomplished by thioketalization of 217delivering 218, which was desulfurized to 219 with Raney-Ni(Scheme 53).98

In conclusion, the reductive desulfurization of thioketals andacetals has been well studied, and can be easily achieved withRaney-Ni, Li/EtNH2, or Li/NH3(liq) as the preferred reducing agents.

7. S-containing functional groups for tuning reactivity

As thiosubstituents can be removed via reductive de-sulfurization in a ‘traceless’ manner leaving a hydrogen behind,such substituents have been used to activate (or tune the reactivityof) reagents and reaction partners.

In this respect, a paradigm changing strategic application ofa desulfurization reaction was the classic synthesis of cantharidin

(223) by Dauben.99 Cantharidin is the active ingredient of theaphrodisiac ‘Spanish Fly’. The attempted DielseAlder-reaction be-tween dimethylmaleic anhydride and furan did not proceedeven at 40 kbar pressure. In contrast, 2,5-dihydrothiophene-3,4-

Scheme 53. Synthesis of (þ)-b-cuparenone (220).


dicarboxylic anhydride (221) reacted smoothly to 222, which isbelieved to result from the less electron-donating character of thethioalkyl substituents and reduced steric demand. Reaction of 222with Raney-Ni reduced the olefinic double bond and removed thesulfur bridge to produce cantharidin (223) (Scheme 54).

Scheme 54. Dauben’s synthesis of cantharidine (223).

In their formal total synthesis of the pyrrolizidine alkaloid(þ)-retronecine (229), Kametani et al. used an intermolecular car-benoid displacement reaction of optically active sulfide 224 withdiazomalonate 225 under Rh(II)-catalysis (Scheme 55).100 De-sulfurization of 226 with Raney-Ni led to 227 without cleaving the

Scheme 55. Synthesis of (þ)-retronecine (229).

Scheme 56. Chlorine atom transfer cyclization.

benzylesters, which was later achieved with Pd/C allowing theconversion into lactone 228, from which an earlier synthesis of(þ)-retronecine (229) had been reported.

Ishibashi et al. have developed a Ru-catalyzed chlorine atomtransfer cyclization of N-allylic a-chloro-a-thioacetamides. Inone example they used substrate 230, which was cyclized to231 with RuCl2(PPh3)2 as a catalyst. Treatment with Raney-Niled to desulfurization and dehalogenation producing the

bicyclic lactam 232 in excellent diastereoselective purity(Scheme 56).101

Kodama et al. used an anion-induced intramolecular cyclizationfor the synthesis of the diterpenoid (rac)-cubitene (236), which hasbeen isolated from the defence secret of the East African termite

Cubitermes umbratus. Deprotonation of allylic sulfide 233 with n-BuLi produced an anion, which attacked the epoxide moiety in-tramolecularly leading to 12-membered ring 234. Desulfurization


of 234with Na in n-BuOH led to 235 in excellent 93% yield withoutcompromising the olefin geometries. Dehydration of the tertiaryalcohol furnished 236 (Scheme 57).102

Scheme 57. Stabilized allyl anion cyclization in the synthesis of (rac)-cubitene (236).

A similar type of intramolecular cyclization was used by Li et al.in their synthesis of (rac)-sarcophytol M (239). Allylsulfide 237wasdeprotonated with LDA forming an allyl carbanion, which attackedthe carbonyl group of the ketone intramolecularly to furnish 14-membered ring 238, which upon desulfurization with Li/EtNH2produced 239 in 78% yield (Scheme 58).103 A similar strategy wasused for the synthesis of isoprenoid chains.104

Scheme 58. Synthesis of (rac)-sarcophytol M (239).

In their synthesis of the ionophore lasalocid A (X537A) Irelandet al. required the intermediate 243, which they planned to achieveby opening the epoxide 240 with a methyl anion synthetic equiv-alent.105 When using lithium dimethyl cuprate, the attack occurredat the more hindered C-17 position producing 241, which was ra-tionalized by precomplexation of the organometallic reagent by theadjacent MOM-protecting group.With lithiated 1,3-dithiane, attackoccurred at the sterically more accessible C-16 position of 240.Reductive desulfurization with Raney-Ni transformed the dithiane242 into the corresponding methyl substituent furnishing 243(Scheme 59).

Scheme 59. Regioselective ring opening of

Building on their observation that b-alkylthio substituents ac-celerate the Rh-catalyzed intermolecular hydroacylation of alkenesand alkynes, Willis et al. exploited this chelation-effect by studying

b-thioketal (five- and six-membered rings) substituted aldehydesas substrates, for which intermediates, such as 247 are postulated.In one application of this reaction aldehyde 244 reacts withmethylacrylate to CeC-fused product 245, which by reductive de-sulfurization can be converted into g-ketoester 246 (Scheme 60).106

In their elegant enantioselective total synthesis of (�)-strych-nine (252) Shibasaki et al. prepared thioacetal 248. In the presence

of 5 equiv DMTSF a thionium ion is formed, which reacts as anelectrophile with the nucleophilic indole producing the C-ring of249. Functional group manipulation furnished 250, which was setfor reductive desulfurization to produce 251. The classic protocoleven with deactivated Raney-Ni W-2 proved unsatisfactory as itpromoted considerable migration of the exocyclic (C19eC20) olefinto the endocylic (C20eC21) alkene. Fortunately, nickel boride ina carefully optimized solvent mixture (EtOH:MeOH 4:1), whichsuppressed overreduction, produced desired 251 in 61% yield. 251could be transformed into target compound (�)-strychnine (252) infour steps (Scheme 61).107,108

epoxides by methyl anion equivalents.

Scheme 60. Thiodirected hydroacylation.

Scheme 61. Shibasaki’s synthesis of (�)-strychnine (252).


Knapp et al. enabled ring expansion of cyclic ketones to 1,2-ketothioketals. This two-step procedure was successfully used toshorten the total synthesis of (�)-coriolin intermediate 260 as wellas selective introduction of a methyl group during this synthesis(Scheme 62).109 The final step in their synthesis towards the(�)-coriolin BC rings 260 involved reduction of the thioketal 259via Raney-Ni.

Schreiber et al. reported desulfurizationwith Raney-NiW-4 thathas been activated by sonication. The thioacetal in the a,a-di-substituted lactone was incorporated to ease the ring-expansion of261, which produced a mixture of 262a and 262b. This mixturewas used in the following reduction with the sonicated Raney-Nitowards the spore germination autoinhibitor gloeosporone(Scheme 63).110

8. S-heterocycles for improved selectivity and molecularrecognition

The traceless removal of sulfur from molecular frameworks notonly allows to use such substituents to control the reactivity inreagents, but also to fix conformational orientations or to imposea steric bias, which has a favourable influence on the selectivity ofreagents.

Stotter et al. have developed a very useful method to fix thegeometry of acyclic olefins through the formation of the olefins aspart of sulfur-containing heterocycles.111 4-Thiacylcohexanone(266) is reacted with carbanion reagents, which after dehydrationproduces cyclic olefin 267. The allylic CH in a-position to sulfur canbe deprotonated and reacted with generic electrophiles to produce

Scheme 62. Ring expansion in the synthesis coriolin intermediate (260).

Scheme 63. Ring expansion in Schreiber’s synthesis towards gloeosporone.


268. Reductive desulfurization ultimately furnishes Z-olefin 269(Scheme 64). They have applied this strategy in the formal totalsynthesis of the Cecropia juvenile hormone 275. Starting from 270and 271 the dithiopyran structure 272 was assembled, which wasfurther elaborated to 273. For the crucial desulfurization a two-stepprotocol was developed. First the allylic CeS bond was cleaved bereduction with lithium in ethylamine at �78 �C, immediately fol-lowed by desulfurization of the resulting mercaptans using Raney-Ni in refluxing EtOH. This protocol is superior to a protocol usingRaney-Ni alone, which suffers from overreduction and double bondisomerization.

Fujisawa et al. used a chemoenzymatic approach for the syn-thesis of rice and weevils aggregation pheromone (�)-(4R,5S)-

sitophilure (278).112 As cyclic 1,3-diketones are more opportunesubstrates than acyclic 1,3-diketones 3-propionyltetrahydrothiopyran-4-one (276) was reduced by bakers’ yeast in very goodenantio- and excellent diastereoselectivity to chiral b-hydrox-yketone 277. Reductive desulfurization using Raney-Ni furnishedpheromone 278 (Scheme 65).

Griengl et al. observed only moderate enantioselectivity of 54%ee in the cyanohydrin formation of ethyl methyl ketone 279 cata-lyzed by the hydroxynitrilase (HNL) from Hevea brasiliensis. Con-sidering a ‘docking/protecting group’ technique the spatialsimilarity of the vicinity in the carbonyl group should be abolished(Scheme 66). Indeed substrates 281 and 285 proved to be excellentsubstrates for the HNL-reaction, producing the cyanohydrins 282

Scheme 64. Synthesis of juvenile hormone (275).

Scheme 65. Chemoenzymatic synthesis pheromone 278.

Scheme 66. Selectivity improvement in HNL-biocatalytic transformation by removable thiosubstituents.



and 286 in 99% ee each, which after hydrolysis and reductive de-sulfurization could be converted into the chiral disubstituted a-hydroxycarboxylic acid 284.113

Another application, in which an enzymatic reaction is followedby a reductive desulfurization has been given by Haufe et al.(Scheme 67).114 Diene 288 is first reacted with dichlorosulfane todeliver the dichloro-thioadamantane 290 in a transannular S-het-erocyclization via episulfonium ion 289. Favoured by anchimericassistance of sulfur, nucleophilic displacement resulted in diol(rac)-291. Kinetic resolution of the racemic mixture by acetylationwith Candida rugosa lipase left behind unreacted enantiomer(þ)-291 consistent with Kazlauskas’ rule of enantiomeric recogni-tion. Reductive desulfurization produced enantiopure 9-oxybicyclo[3.3.1]nonane-2,6-diol (þ)-292.

Scheme 67. Synthesis of enantiopure 9-oxybicyclo[3.3.1]nonane-2,6-diol ((þ)-292).

Ward et al. influenced significantly the synthetic methods topolypropionate derivatives by developing a thiopyran based strat-egy.115 The main strength of this template based synthesis is thethiopyran induced establishment of stereocentres followed bysimple desulfurization to obtain complex natural products andanalogues. With this strategy, Ward et al. were able to synthesizefor example, serricornin (298), siphonarin B (306) and baconipyr-ones A (307) and C (308) (Scheme 68).116e118 All syntheses startwith two functionalized thiopyranes 293 and 294 or 299, whichundergo an enantioselective aldol reaction. After desired func-tionalization of the resulting thiopyran motif 295, desulfurizationtakes place in 82% yield followed by deprotection to obtain serri-cornin (298). In the synthesis of baconipyrone A (307) and C (308)and siphonarin B (306), the protected aldol product 300 wasdesulfurized directly in 86% yield. The subsequent functionalizationgave 302, which underwent another aldol reaction with thiopyranmotif 303. Treatment with Raney-Ni resulted in double reductivedesulfurization and deprotection in one step. After selectivetransformations either siphonarin B (306), baconipyrone A (307) orbaconipyrone C (308) were obtained.

Soai et al. have used a twofold reductive desulfurization ofthiophene substituents at a quaternary stereogenic centre for theproduction of the chiral but optically inactive (‘cryptochiral’) nat-urally occurring alkane (R)-310.119 The differently substitutedthiophene rings were essential for resolution of the racemic mix-ture (rac)-309 via HPLC on a chiral stationary phase (Scheme 69).310 does not show ameasurable optical resolution, but controls the

absolute configuration in the asymmetric autocatalytic reaction ofsubstrate 311 leading to product and autocatalyst 312.

Schmalz reported about an elegant synthesis of the marinenatural product (þ)-ptilocaulin (318) with the chiral h6-arene-Cr(CO)3 complex 313 as a synthetic building block. Lithiated 1,3-dithiane (314) served as a C1-building block attacking 313 to pro-duce cyclohexenone 315 in 99% ee. Functional group manipulationled to 316, which upon reductive desulfurization with Raney-Nifurnished 317, which was elaborated to 318 (Scheme 70).120

Taking together the work of Ward et al. provides convincingshowcases, which illustrate the efficiency of using the combinationof S-heterocycles/reductive desulfurization as a strategic tool toimprove the selectivity of reactions. This methodology has alreadyshown its value in the synthesis of complex natural products.

9. Acyclic S-compounds for improved selectivity and molec-ular recognition

In a similar manner to the strategy described in Chapter 7 alsoacyclic S-compounds have found application as a control elementin stereoselective reactions.

The selective a-alkylation of ketones is an important tool in thesynthesis of polycyclic natural products. Ireland and Marshall haveintroduced in 1962 a viable strategy to this problem by introducingthe n-butylthiomethylene blocking group, which after serving itsfunction can be either removed by basic hydrolysis or convertedinto a methyl group via reductive desulfurization. Using 2-methylcyclohexanone as a model substrate they could convertthe central intermediate 321 into the differently methylated cy-clohexanones 323e325 (Scheme 71).121

Using the methodology developed earlier by Paterson andFleming,122 Tamura et al. reported an efficient synthesis of methyldihydrojasmonate (321) starting from cyclopentenone (326).Reaction with silylketene acetal 327 introduced the ester sidechain with concomitant formation of the silylenolate 328. 328reacted in the presence of TiCl4 with the highly electrophilicchlorosulfide 329 resulting in a-substituted 330. The ancillaryphenylthio group was removed by reductive desulfurization withRaney-Ni producing the dihydrojasmonate first as a mixture ofcis/trans diastereomers, which was easily transformed intopure trans-product 331 via epimerization with triethylamine(Scheme 72).123

Scheme 68. Ward’s syntheses of polypropionate natural products using his tetrahydropyran methodology.

Scheme 69. Asymmetric autocatalysis triggered by cryptochiral alkane 310.


Scheme 70. Schmalz’ synthesis of (þ)-ptilocaulin (318).

Scheme 71. Regioselective alkylation through n-butylthiomethylene blocking groups.

Scheme 72. Synthesis of dihydrojasmonate 331.



Schaumann et al. reported about an elegant and efficient syn-thesis of (þ)-artemeseole, a compound identified in the essentialfrom Artemisia tridentata. Deprotonation of allylphenylsulfide withn-BuLi generated an allyl anion, which reacted with epoxide 332 toproduce among other isomers homoallylic alcohol 333. Functionalgroup manipulation furnished key intermediate 334. Anion gen-eration via the radical anion lithium di-tert-butylbiphenyl (LiDBB)instantaneously led to cyclopropane ring closure providing 335,which under acid catalysis was transformed into (þ)-artemeseole(336) (Scheme 73).124

Scheme 73. Synthesis of (þ)-artemeseole (336).

Nicolaou et al. have developed a universal strategy for thestereocontrolled construction of 2-deoxy glycosides. The anomericcentre is controlled by the stereoconfiguration of a phenylthiosubstituent, which is subsequently removed (Scheme 72).125 Animpressive application of this strategy is the synthesis of Sialyl LeX

(345). Glycosylation of 342 with intermediate 341 furnishes tetra-saccharide 343. Reductive desulfurization was achieved withPh3SnH/AIBN in refluxing toluene in 77% accompanied with for-mation of the d-lactone 344. Protecting group manipulation led toSialyl LeX (345) (Scheme 74).

This strategy was also used by Roush et al. in their synthesis ofthe C-D-E trisaccharide subunit of the natural product olivomy-cin.126 After assembly of the trisaccharide 346 the tosyl groups of346 were first converted into iodides via SN2 displacement. Sub-sequent treatment with Raney-Ni not only reductively removed thephenylthio group but also dehalogenated the iodides to producethe C-D-E trisaccharide subunit of olivomycin 347 protected as thetrimethylsilylethylether (Scheme 75).

Nakayama et al. used a thioether linkage to turn a notoriouslyunselective intermolecular pinacol coupling between ketones intoa highly selective intramolecular pinacol coupling of easily pre-pared diketosulfides 348, in which the cis-diol intermediates 349are produced.127 Depending on the alkyl substituents, de-sulfurizationwith Raney-Ni furnishes the erythro- or threo-1,2-diols350 (Scheme 76). With this approach also unsymmetrical diols 353are accessible, which otherwise would produce mixtures in theintermolecular pinacol coupling. If thiophenes are introduced assubstituents in the substrate 354, then the subsequent de-sulfurization delivers the corresponding alkyl products 356.

H€ogberg et al. identified conditions, which allow the highlydiastereoselective addition of organozinc reagents to 2-alkyl-3-

(arylsulfanyl)propanals exploiting the chelating property of thephenylthio group. Reaction of aldehyde 357 with Me2Zn inthe presence of TiCl4 furnished alcohol 358 with high anti-Cramselectivity. Reductive desulfurization produced the pinesawfly pheromone component 359 by converting the phenyl-thiomethyl substituent into a methyl group (Scheme 77).128 Itshould be noted that the methyl group itself could not havebeen introduced with the desired diastereoselectivity in theorganozinc addition as it would lack the chelating abilityand also exerts only a small steric influence, again showcasing

the stereoselectivity gain made possible by using thioethergroups.

Mikami et al. used their BINOL/TiCl2(Oi-Pr)2 catalyst system129

for a two directional asymmetric ene reaction with fluoral (360)and enesulfide 361 to produce a mixture of isomers of doublereacted products with anti,Z-363 and anti,E-363 as main products,which upon reductive desulfurization and hydrogenation withRaney-Ni convergently reacted to diol 364, which found useas tether in antiferroelectronic liquid crystalline molecules(Scheme 78).130

In their synthesis of corynantheine (368) Autrey and Scullardused the methylthio substituent in 365 to guide the Beckmannfragmentation to produce 366. In order to convert 366 to olefin 367they faced the challenge to desulfurize a vinylsulfide in the pres-ence of a nitrile and without reducing the desired olefin. It requiredconsiderable optimization to identify the optimal conditions withRaney-Ni in refluxing MeOH to produce the desired compound 367in excellent 82% yield (Scheme 79).131

The enantioselective protonation of enolates represents a highlydesirable transformation for creating new stereogenic centres.However, current methodology faces selectivity problems. Tomiokaet al. have reported about a very interesting two-step procedure,which combines a 1,4-addition of a bulky thiolate 371 to the ac-rylate 369 in the presence of chiral modifier 370 resulting in anenolate 372, which is immediately protonated by the correspond-ing thiol 373. Reductive desulfurization of the thioether 374 withRaney-Ni produced chiral esters 375 without any epimerization(Scheme 80).132

Singh et al. showed a similar reaction but with the advantage ofusing just 1% chiral thiourea catalyst 377 instead of a chiral reagentfor the enantioselective thia-Michael addition. As an application of

Scheme 74. Phenylthio-controlled glycosylation in the synthesis of Sialyl LeX (345).

Scheme 75. Synthesis of the C-D-E trisaccharide subunit of olivomycin.


their highly selective reaction they showed a synthesis of (S)-ibu-profen (379). Thia-Michael reaction of PhSH to acrylamide 376under catalysis with 377 occurred in 92% ee. Reductive de-sulfurization with Raney-Ni and saponification led to 379 in 52%yield (Scheme 81).133

Node et al. developed a domino-Michael addition/Meer-weinePonndorfeVerley (MVP) reduction, which formally repre-sents a highly enantioselective reduction of a,b-unsaturatedketones to secondary alcohols.134 a,b-Unsaturated ketone 380 re-acts first in a thia-Michael addition with chiral camphor-derivedthiol 381 under Me2AlCl-mediation. Intermediate 382 ideally

positions the hydrogen of the isoborneol for an 1,7-hydride shift inanalogy to an intramolecular MVP-reduction to produce 383. Theauthors comment that with aromatic substituents at position R1

and R2 desulfurization with Raney-Ni to 384 occurred without ra-cemization of the secondary alcohol in hypophosphite bufferedEtOH solution, whereas this method did not proceed for aliphaticsubstituents. For these the secondary alcohol had first to be pro-tected as benzoate esters and then Raney-NiW-2 in EtOH produced384 to avoid epimerization (Scheme 82).

(�)-Pyrimidoblamic acid (389) was a central intermediate in thesynthesis of deglycobleomycin A2 by the Boger group. The tin

Scheme 76. Selectivity gain via thio-tethered intramolecule pinacol coupling.

Scheme 77. Phenylthio-substituents enabling a switch to chelate controlled addition selectivity.

Scheme 78. Improved selectivity in asymmetric ene reaction.


enolate 386 reacted with imine 385 to furnish coupling product387. The methylthio group, which had served its purpose as a se-lectivity improving group in the previous step, was removed underradical conditions using Bu3SnH/AIBN in refluxing benzene toproduce 388 (Scheme 83).135

Nagao et al. have developed a method, in which under softenolization conditions chiral tin enolates are formed from 390,which react with iminium species generated from precursor 391 toform coupling product 392. Reductive desulfurization with Raney-Ni in refluxing EtOH occurred under concomitant cleavage of the

Scheme 79. Thiosubstituent directed Beckmann-fragmentation.

Scheme 80. Enantioselective protonation of acrylates induced by a thia-Michael addition.


auxiliary to furnish 393, which upon saponification produced(þ)-ecgoninic acid (394) (Scheme 84).136

10. Other applications in organic synthesis

In their attempt to synthesize the major metabolite 398 ofprostaglandin D2 Corey et al. faced the challenge to reduce the a,b-unsaturated enone of 395 in the presence of a thioketal anda nonconjugated olefin.137 This was accomplished by first 1,4-

addition of H2S to the a,b-unsaturated enone forming a b-mer-captoenone 396, which was desulfurized with n-Bu3P under pho-tolytic conditions via a C-radical to give 397 in 65% overall yield(Scheme 85).

In their total synthesis of a-berbatene (402) Ito et al. trans-formed the dimesylate 399 into tetrahydrothiophene 400, whichwas desulfurized with lithium in ethylamine in the presence of 2-propanol leaving the olefin moiety intact. 401 was then trans-formed into 402 via skeletal rearrangement (Scheme 86).138

Scheme 81. Synthesis of (S)-ibuprofen (379) via enantioselective organocatalytic thia-Michael addition.

Scheme 82. Intramolecular MVP-reduction.

Scheme 83. Synthesis of (�)-pyrimidoblamic acid (389).


Scheme 84. Synthesis of (þ)-ecgoninic acid (394).

Scheme 85. Chemoselective reduct



Applying a transformation introduced by Djerassi et al.139 forsteroids Masjedizadeh from Syntex succeeded in the de-sulfurization of thiazolidinone 404 into enamide 405, which ulti-mately could be transformed into chiral (S)-2-aminoquinuclidine(406) (Scheme 87). This synthesis sequence was applicable toprepare tritiated variants of 406.140

Reductive desulfurization can also be used for the de-oxygenation of alcohols, if the alcohol is first converted into a thiolor thioether. Fukumoto et al. used a clever arrangement of Sharp-less asymmetric epoxidation of 407 to produce a highly strainedoxaspiropentane, which readily converts into cyclobutanone 408upon acid-catalyzed 1,2-rearrangement. Removal of the hydroxygroup was achieved in a two-step procedure involving the de-sulfurization of the phenylthio group producing 410. 410 wasconverted into (þ)-a-cuparenone (411) in an one-pot reaction fol-lowing a previously established protocol (Scheme 88).141

For their synthesis of the marine natural product avarol (418)Theodorakis et al. developed a fascinating radical CeC couplingreaction. Starting from carboxylic acid 412 the Barton ester 413wassynthesized, which upon photolysis produced radical 414. 414 im-mediately reacted in conjugate type addition with benzoquinone415 resulting in 416, which with an excess of 415 furnished the

ion of a,b-unsaturated ketone.

a-berbatene (402).

Scheme 87. Synthesis of enamide via reductive desulfurization.

Scheme 88. Synthesis of (þ)-a-cuparenone (411).


isolable derivative 417 in 81% yield. Reductive desulfurization re-moved the 2-pyridylthio substituent and reduced the quinonemoiety producing avarol (418) in very good yield (Scheme 89).142

Steroid scaffolds were synthesized by Njardarson et al. by usingthiopyran building blocks, which were synthesized via one-pot

Scheme 89. Synthesi

anionic cascade reaction, which involves an S/O group transferreaction. By reacting 419 with vinyl-Grignard reagent in the pres-ence of CeCl3 the C]O group is nucleophilically attacked to give thedivinyl carbinol, that is, treated with KOtBu creating an oxyanion,which reacts with the phosphorous atom furnishing a thiolate

s of avarol (418).


anion, which undergoes a 6-endo-trig cyclization to produce 420. ADielseAlder reaction of 420 with dienophile 421 produced 422,which either upon reductive desulfurization with Raney-Ni resul-ted in descarba-steroid 423 or could be ring contracted to steroidderivative 424 (Scheme 90).143

Scheme 90. Synthesis of steroid analoga.

Olefins can be activated by reactionwith sulfenium reagents, fornucleophilic attack, which results in products with an RS-substituent, which can later be removed by reductivedesulfurization.

In a synthetic study towards the antiimmunosuppressiveagent FR901483 Weinreb et al. accomplished the PhSClinduced cyclization of homoallylic amine 424 to tricyclic structure425, which was smoothly desulfurized to product 426(Scheme 91).144

Scheme 91. PhSCl-induced cyclization of homoallylamines.

Livinghouse et al. converted the acyclic precursor 427 viaa sulfenium ion promoted cascade annulation into tricycle 428.Efforts towards the selective desulfurization of the phenylthiosubstituents in 428 with Raney-Ni or lithium amalgam led topartial reductive cleavage of the benzylic cyano substituent. Thetransformation of 428 to 429 was finally accomplished in 94%overall yield by protecting first the nitrile function as its lithioderivative, allowing the reductive desulfurization with lithiumnaphthalenide and final oxidative decyanation to deliver429. Dealkylation with BBr3 furnished (rac)-nimbidiol (430)(Scheme 92).145

For their synthesis of (rac)-18-noraspidospermidine (434) thegroup of Rodriguez used a Pummerer rearrangement of acylsulfinylderivative 431 to form cyclization product 432. The reactionmechanism is believed to proceed through a sulfenium in-termediate, which electrophilically attacks the electron rich indole

ring. Reductive desulfurization of 432 with Raney-Ni furnished433 in 82% yield. 433 was then reduced with LiAlH4 to 434(Scheme 93).146

Magnusson et al. synthesized a series of enantiomerically purelignans by diastereoselective 1,4-addition of the dithioacetal anion436 to a,b-unsaturated ketone 435. In this example reductive de-sulfurization of 437 with Raney-Ni followed by deoxygenationwith Pd/C in AcOH led to (þ)-burseran (438) in 52% yield(Scheme 94).147

In a study aiming at the synthesis of lactones of tyrosineand other amino acids Rao et al. needed intermediate 442,which should be prepared by reductive desulfurization of 441.The standard reagent Raney-Ni in various solvents as wellas a variety of hydride reducing agents proved to be inefficient.Ultimately either radical desulfurization with Bu3SnH orrefluxing with Hantzsch ester produced 442 in good yields(Scheme 95).148

Saito et al. have developed a stereoselective hetero-DielseAlderreaction between thiochalcones, such as 443 with dimenthylfu-marate 444 to furnish 3,4-dihydrothiopyranes, which upon

Scheme 92. Synthesis of (rac)-nimbidiol (430).

Scheme 93. Synthesis of (rac)-18-noraspidospermidine (434).

Scheme 94. Synthesis of the lignan (þ)-burseran (438).


Scheme 95. Selective desulfurization methods in the presence of sensitive functional groups.


reduction of the ester groups produced 445. Reductive de-sulfurization with Raney-Ni resulted in optically pure diol 446(Scheme 96).149

In a study towards the synthesis of pseudoguainolides McKer-vey et al. treated 447with Raney-Ni, which led to desulfurization of

Scheme 96. Diastereoselective DielseAlder reaction.

the butylthio group, debromination and hydrogenation of the olefindelivering 448 in 68% yield (Scheme 97).150

In a study aiming at the synthesis of carbapenems Natsugariet al. had to investigate the desulfurization of intermediate 449.They observed an interesting case of stereoselective control

Scheme 97. Desulfurization producing lactone 448.

depending on the used desulfurization agent. With Raney-Ni theyisolated trans-azetidinone 450 as the major product (47% isolatedyield) together with 21% of cis-azetidinone 451. In contrast Bu3SnHwith AIBN as a radical initiator yielded preferentially cis-azetidi-none 451 in 72%, with 450 as a by-product in 22% yield(Scheme 98).151

The desulfurization of alkylthio-DNA adducts with Raney-Ni hasrecently been used for the development of an assay of 1,2-dibromoethane-derived DNA crosslinks formed with O6-alkylgua-nine-DNA alkyltransferase.152

11. Reductive desulfurization in peptide chemistry

Recent developments in peptide chemistry have allowed thetotal synthesis of proteins. Instrumental for this amazing de-velopment was an efficient assembly strategy with which un-

protected peptide fragments (resulting from solid phase peptidesynthesis or recombinant expression) are connected via nativechemical ligation (NCL) developed by Kent et al. In NCL a peptidefragment with a C-terminal thioester 452 undergoes first a trans-thioesterification with a peptide fragment 453 exhibiting an N-terminal cysteine (Cys) resulting in thioester 454, which in an

Scheme 98. Diastereoselective control in the synthesis of azetidinones via desulfurization.


intramolecular S- to N-acyl shift furnishes the thermodynamicallymore stable peptide 455 (Scheme 99).153

Due to its efficiency the NCL has soon found application in thetotal synthesis of proteins, such as HIV-protease, Ras, and others. A

Scheme 99. Native chemical ligation (NCL) of peptide fragments.

considerable limitation however was the requirement to have a Cysat the ligation site, because Cys is the least abundant of all protei-nogenic amino acids. By building on earlier work by Perlstein et al.who have demonstrated that proteins can be desulfurized withRaney-Ni,154 Dawson and Yan have found a very convenient way of

extending the scope of NCL in converting the introduced Cys ofcoupled peptide 455 into an alanine (Ala) of 456 via reductive de-sulfurization (Scheme 100).155 They showcased this strategy ina synthesis of the peptide antibiotic microcin J25 (459). Intra-

molecular NCL of the acyclic precursor 457 furnished cyclizationproduct 458 in 50% isolated yield, which could be quantitativelytransformed into 459 by reductive desulfurization with eitherRaney-Ni or Pd/Al2O3. When using other peptide substrates theauthors noted that prolonged treatment with Raney-Ni is

Scheme 100. Synthesis of microcin J25 (459) via NCL and reductive Cys-to-Ala conversion.


accompanied with desulfurization of methionine (M), whereas Pd/Al2O3 can lead to hydrogenation of tryptophan (W).

As the desulfurization with Raney-Ni or Pd/C imposessome restrictions on the use of protecting or activating groups,Danishefsky et al. developed a homogeneous radical desulfurization method with triethylphosphite (or trialkylphosphine) anda radical initiator for peptides and proteins, by adapting method-ology developed earlier for small molecule synthesis(Scheme 101).156e159

Scheme 101. Catalytic cycle for the radical desulfurization of thiols.

In the optimization process for this reaction Danishefsky re-alized that yields and selectivity are best, if the water-solubletris(2-carboxyethyl)phosphine (TCEP) and the water-soluble rad-ical initiator VA-044 is used, which has the additional advantage ofhaving a very low temperature of decomposition.160 With thisreaction combination it is possible to perform the Cys/Alatransformation in the presence of Met, biotin, Cys(Acm), thiazoli-dines, and many other functionalities. The unique selectivity oftheir new method proved instrumental for Danishefsky’s suc-cessful total synthesis of a homogeneous erythropoietin (EPO)with the native sequence of 166 amino acids and chitobioseglycanresidues.161

Over the last years, several b-thio and g-thio substitutedamino acids have been synthesized, which offer new opportuni-ties for identifying other ligation sites, which after radical de-sulfurization produce natural amino acids. As this topic has beenreviewed by Dawson162 and Seitz163 only a few examples arenamed here. The groups of Seitz164 and Danishefsky165 have in-troduced the amino acids 460 and 461, which serve as N-terminalligating units delivering peptides, which upon radical de-sulfurization are converted into peptide 464 with Val at the li-gation site (Scheme 102).

In addition thiolated amino acid 465 enables the proline (Pro)-ligation,166 466 the phenylalanine (Phe)-ligation,167 and 467 thelysine (Lys)-ligation in combination with radical desulfurization(Scheme 103).168

Very recently Payne et al. have reported an aspartate (Asp)-li-gation, which tolerates unprotected Cys as the desulfurization oc-curs without an added initiator because the homolytic cleavage ofthe CeS bond at the thiolated Asp should be two orders of mag-nitudes faster than in the Cys. An example is given in Scheme 104for the ligation of peptides 468 and 469 and the in situ initiator-

Scheme 104. Asp-ligation and initiator-free desulfurization.

Scheme 102. Amino acids for the Val-peptide ligation.

Scheme 103. Amino acids used for Pro-, Phe-, and Lys-ligation.


free desulfurization with TCEP furnishing peptide 470 in 63%yield.169

These selected examples show that new ligation strategies en-abled by several new thiol-substituted amino acids in combinationwith TCEP/VA-044 as a very mild and highly efficient de-sulfurization reagent are making an enormous impact in the syn-thesis of peptides, proteins and posttranslationally modifiedprotein structures.

12. Conclusions

In this review we have shown that S-containing compoundshave found widespread application in organic synthesis as they canbe used as Cn-building blocks, are able to regulate the reactivity ofreagents, help to control the stereochemical outcome of reactions,or are reactive handles to stitch reaction partners together. Oncesuch elements have served its purpose they can be removed byreductive desulfurization in a traceless manner, leaving only a hy-drogen atom behind, which offers tremendous flexibility in the

strategic use of such elements in synthetic planning. For the futurewe hope that an even more efficient and milder reagent thanRaney-Ni (ideally in the form of a catalyst) will be identified, whichallows the reductive desulfurization of thiophenes and thio-ethers.170 Currently, Raney-Ni is without alternative as a reagent forthiophenes. For thioethers it can be complementedwith Li in aminesolvents, which itself has its limitations as a reagent. The recentdiscovery of the reagent combination TCEP/VA-044, which hasrevolutionized the desulfurization of thiols due to its efficiency and

functional group tolerance, shows that such innovations are stillpossible.

Acknowledgements

Our own research in this field was supported by grants ofPLACEBO (Platform for Chemical Biology) project as part ofthe Austrian Genome Project GEN-AU funded by the For-schungsf€orderungsgesellschaft (FFG) and Bundesministerium f€urWissenschaft und Forschung (BMWF) and NAWI Graz.

Abbreviations

Acm acetamidomethylACN acetonitrileAIBN 2,20-azobis(isobutyronitrile)Bn benzylBz benzoyl


CSA camphorsulfonic acidDABCO diazabicyclo[2.2.2]octaneDBU 1,8-diazabicycloundec-7-eneDEAD diethylazodicarboxylateDCC N,N0-dicyclohexylcarbodiimideDCM dichloromethaneDFT density functional theoryDMAc N,N-dimethylacetamideDME 1,2-dimethoxyethaneDMTSF dimethyl(methylthio)sulfonium tetrafluoroboratedppe bis(diphenylphosphino)ethaneEE ethoxyethylEMK ethylmethylketoneGn guanidiniumLiDBB lithium 4,40-di-tert-butylbiphenylm-CPBA meta-chloroperbenzoic acidMOM methoxymethylPiv pivaloylPLE pig liver esterasePPTS pyridinium para-toluenesulfonateTFAA trifluoroacetic anhydrideTBMDS tert-butyldimethylsilylTCEP triscarboxyethylphosphineTMS trimethylsilylTMSE trimethylsilylethylUHV ultrahigh vacuumVA-044 2,20-azobis[2-2-(imidazolin-2-yl)propane]

dihydrochlorideXAS X-ray absorption spectroscopyXPS X-ray photoelectron spectroscopy

References and notes

1. Petit, G.; van Tamelen, E. Org. React. 1962, 12, 365e529.2. Hauptmann, H.; Walter, F. W. Chem. Rev. 1962, 62, 347e404.3. Belen’kii, L. I.; Gol’dfarb, Y. L. In The Chemistry of Heterocyclic Compound;

Weissberger, A., Ed.; Wiley-Interscience: New York, 1986; Vol. 44/I,pp 457e569.

4. Najera, C.; Yus, M. Tetrahedron 1999, 55, 10547e10658.5. Alonso, D. A.; Najera, C. Org. React. 2008, 72, 376e656.6. Kuehm-Cauber, C.; Guilmart, A.; Adach-Becker, S.; Fort, Y.; Caubere, P. Tetra-

hedron Lett. 1998, 39, 8987e8990.7. Becker, S.; Fort, Y.; Caubere, P. J. Org. Chem. 1990, 55, 6194e6198.8. Graham, T. H.; Liu, W.; Shen, D.-M. Org. Lett. 2011, 13, 6232e6235.9. Barbero, N.; Martin, R. Org. Lett. 2012, 14, 796e799.

10. Matsumara, T.; Niwa, T.; Nakada, M. Tetrahedron Lett. 2012, 53, 4313e4316.11. Mozingo, R.; Wolf, D. E.; Harris, S. A.; Folkers, K. J. Am. Chem. Soc. 1943, 65,

1013e1016.12. Fonken, G. S.; Mozingo, R. J. Am. Chem. Soc. 1947, 69, 1212e1213.13. Harris, S. A.; Mozingo, R.; Wolf, D. E.; Wilson, A. N.; Folkers, K. J. Am. Chem. Soc.

1945, 67, 2102e2106.14. du Vigneaud, V.; Melville, D. B.; Folkers, K.; Wolf, D. E.; Mozingo, R.; Keresz-

tesy, J. C.; Harris, S. A. J. Biol. Chem. 1942, 146, 475e485.15. Hofmann, K.; Zhang, W. J.; Romovacek, H.; Finn, F. M.; Bothner-By, A. A.;

Mishra, P. K. Biochemistry 1984, 23, 2547e2553.16. Wolfrom, M. L.; Karabinos, J. V. J. Am. Chem. Soc. 1944, 66, 909e911.17. Blicke, F. F.; Sheets, D. G. J. Am. Chem. Soc. 1949, 71, 4010e4011.18. Papa, D.; Schwenk, E.; Ginsberg, H. F. J. Org. Chem. 1949, 14, 723e731.19. Covert, L. W.; Adkins, H. J. Am. Chem. Soc. 1932, 54, 4116e4117.20. Mozingo, R. Org. Synth. 1941, 21, 15.21. Mozingo, R. Organic Syntheses, 1955, Collect. Vol. No. 3, p 181.22. Adkins, H.; Pavlic, A. A. J. Am. Chem. Soc. 1947, 69, 3039e3041.23. Adkins, H.; Billica, H. R. J. Am. Chem. Soc. 1948, 70, 695e698.24. Raney, M. U.S. Patent 1,628,190, 1927.25. Hu, H.; Qiao, M.; Xie, F.; Fan, K.; Lei, H.; Tan, D.; Bao, X.; Lin, H.; Zong, B.;

Zhang, X. J. Phys. Chem. B 2005, 109, 5186e5192.26. Chu, X.; Guo, P.; Pei, Y.; Yan, S.; Hu, H.; Qiao, M.; Fan, K.; Zong, B.; Zhang, X. J.

Phys. Chem. C 2007, 111, 17535e17540.27. Huntley, D. R.; Mullins, D. R.; Wingeier, M. P. J. Phys. Chem. 1996, 100,

19620e19627.28. Huang, L.; Wang, G.; Qin, Z.; Dong, M.; Du, M.; Ge, H.; Li, X.; Zhao, Y.; Zhang, J.;

Hu, T.; Wang, J. Appl. Catal., B 2011, 106, 26e38.29. Morin, C.; Eichler, A.; Hirschl, R.; Sautet, P.; Hafner, J. Surf. Sci. 2003, 540,

474e490.30. Zhu, H.; Guo, W.; Li, M.; Zhao, L.; Li, S.; Li, Y.; Lu, X.; Shan, H. ACS Catal. 2011, 1,

1498e1510.

31. Angelici, R. J. Organometallics 2001, 20, 1259e1275.32. Vicic, D. A.; Jones, W. D. J. Am. Chem. Soc. 1999, 121, 7606e7617.33. Eisch, J. J.; Hallenbeck, L. E.; Han, K. I. J. Am. Chem. Soc. 1986, 108, 7763e7767.34. Gol’dfarb, Y. L.; Fabrichnyi, B. P.; Shalavina, I. F. Tetrahedron 1962, 18, 21e36.35. Catoni, G.; Galli, C.; Mandolini, L. J. Org. Chem. 1980, 45, 1906e1908.36. Stetter, H.; Rajh, B. Chem. Ber. 1976, 109, 534e540.37. Gronowitz, S.; Klingstedt, T.; Svensson, L.; Hansson, U. Lipids 1993, 28,

889e897.38. Dragas, D.; Tanojo, H.; Brussee, J.; Junginger, H. E.; Bodde, H. E. Arch. Pharm.

1996, 329, 465e467.39. Peakman, T. M.; Damste, J. S. S.; De Leeuw, J. W. J. Chem. Soc., Chem. Commun.

1989, 1105e1107.40. Fr€oßl, C.; Boland, W. Tetrahedron 1993, 49, 6613e6618.41. Tsuzuki, H.; Mukumoto, M.; Tsukinoki, T.; Mataka, S.; Tashiro, M.; Yonemitsu,

T.; Nagano, Y. J. Labelled Compd. Radiopharm. 1994, 34, 1087e1090.42. Mohr, J. T.; Gribble, G. W.; Lin, S. S.; Eckenhoff, R. G.; Cantor, R. S. J. Med. Chem.

2005, 48, 4172e4176.43. Goodman, M. M.; Knapp, F. F., Jr.; Elmaleh, D. R.; Strauss, H. W. J. Org. Chem.

1984, 49, 2322e2325.44. Jefferson, A.; Sargent, M. V.; Wangcharoentrakul, S. Aust. J. Chem. 1998, 41,

19e25.45. Noe, C. R.; Knollm€uller, M.; Dungler, K.; G€artner, P. Monatsh. Chem. 1991, 122,

185e194.46. Bracher, F.; Papke, T. J. Chem. Soc., Perkin Trans. 1 1995, 2323e2326.47. Takeshita, M.; Tashiro, M.; Tsuge, A. Chem. Ber. 1991, 124, 1403e1409.48. Sone, T.; Sato, K.; Ohba, Y. Bull. Chem. Soc. Jpn. 1989, 62, 838e844.49. Kurata, H.; Rikitake, N.; Okumura, A.; Oda, M. Chem. Lett. 2004, 33, 1018e1019.50. Hayashi, S.-y.; Inokuma, Y.; Easwaramoorthi, S.; Kim, K. S.; Kim, D.; Osuka, A.

Angew. Chem., Int. Ed. 2010, 49, 321e324.51. Dewar, M. J. S.; Marr, P. A. J. Am. Chem. Soc. 1962, 84, 3782e3782.52. Campbell, P. G.; Marwitz, A. J. V.; Liu, S.-Y. Angew. Chem., Int. Ed. 2012, 51,

6074e6092.53. Collins, M. A.; Jones, D. N. Tetrahedron Lett. 1995, 36, 4467e4470.54. Jacobi, P. A.; Frechette, R. F. Tetrahedron Lett. 1987, 28, 2937e2940.55. Marchalin, S.; Zuziova, J.; Kadlecikova, K.; Safar, P.; Baran, P.; Dalla, V.; Daich, A.

Tetrahedron Lett. 2007, 48, 697e702.56. Safar, P.; Zuziova, J.; Marchalin, S.; Tothova, E.; Pronayova, N.; Svorc, L.; Vrabel,

V.; Daich, A. Tetrahedron: Asymmetry 2009, 20, 626e634.57. Safar, P.; Zuziova, J.; Bobosikova, M.; Marchalin, S.; Pronayova, N.; Comesse, S.;

Daich, A. Tetrahedron: Asymmetry 2009, 20, 2137e2144.58. Tusbuki, M.; Matsuo, S.; Honda, T. Tetrahedron Lett. 2008, 49, 229e232.59. Krishna, P. P.; Lavanya, B.; Ilangovan, A.; Sharma, G. V. M. Tetrahedron:

Asymmetry 2000, 11, 4463e4472.60. Lee, J. S.; Lee, D. J.; Kim, B. S.; Kim, K. J. Chem. Soc., Perkin Trans. 1 2001,

2274e2780.61. Doucet-Personeni, C.; Bentley, P. D.; Fletcher, R. J.; Kinkaid, A.; Kryger, G.; Pi-

rard, B.; Taylor, A.; Taylor, R.; Viner, R.; Silman, I.; Sussman, J. L.; Greenblatt, H.M.; Lewis, T. J. Med. Chem. 2001, 44, 3203e3215.

62. Yang, S.-M.; Nandy, S. K.; Selvakumar, A. R.; Fang, J.-M. Org. Lett. 2000, 2,3719e3721.

63. Rentner, J.; Breinbauer, R. Chem. Commun. 2012, 10343e10345.64. Caputo, R.; Palumbo, G.; Pedatella, S. Tetrahedron 1994, 50, 7265e7268.65. Caputo, R.; Longobardo, L.; Palumbo, G.; Pedatella, S. Tetrahedron 1996, 52,

11857e11866.66. Caputo, R.; Guaragna, A.; Palumbo, G.; Pedatella, S. J. Org. Chem. 1997, 62,

9369e9371.67. Caputo, R.; Festa, P.; Guaragna, A.; Palumbo, G.; Pedatella, S. Carbohydr. Res.

2003, 338, 1877e1880.68. Caputo, R.; Guaragna, A.; Palumbo, G.; Pedatella, S. Phosphorus, Sulfur Silicon

Relat. Elem. 1999, 153e154, 409e410.69. Caputo, R.; De Nisco, M.; Festa, P.; Guaragna, A.; Palumbo, G.; Pedatella, S. J.

Org. Chem. 2004, 69, 7033e7037.70. D’Alonzo, D.; Guaragna, A.; Napolitano, C.; Palumbo, G. J. Org. Chem. 2008, 73,

5636e5639.71. Guaragna, A.; D’Alonzo, D.; Paolella, C.; Napolitano, C.; Palumbo, G. J. Org.

Chem. 2010, 75, 3558e3568.72. Guaragna, A.; D’Errico, S.; D’Alonzo, D.; Pedatella, S.; Palumbo, G. Org. Lett.

2007, 9, 3473e3476.73. Gualandi, A.; Emer, E.; Capdevila, M. G.; Cozzi, P. G. Angew. Chem., Int. Ed. 2011,

50, 7842e7846.74. Gualandi, A.; Petruzziello, D.; Emer, E.; Cozzi, P. G. Chem. Commun. 2012,

3614e3616.75. Petruzziello, D.; Gualandi, A.; Jaffar, H.; Lopez-Carrillo, V.; Cozzi, P. G. Eur. J.

Org. Chem. 2013, 4909e4917.76. Smith, A. B., III; Adams, C. M. Acc. Chem. Res. 2004, 37, 365e377.77. Yus, M.; N�ajera, C.; Foubelo, F. Tetrahedron 2003, 59, 6147e6212.78. Smith, A. B., III; Kim, D.-S. Org. Lett. 2004, 6, 1493e1495.79. Smith, A. B., III; Kim, D.-S. J. Org. Chem. 2006, 71, 2547e2557.80. Leung, L. M. H.; Boydell, A. J.; Gibson, V.; Light, M. E.; Linclau, B. Org. Lett. 2005,

7, 5183e5186.81. Leung, L. M. H.; Gibson, V.; Linclau, B. J. Org. Chem. 2008, 73, 9197e9206.82. Wang, Y.; Dai, W.-M. Tetrahedron 2010, 66, 187e196.83. Ramig, K.; Kuzemko, M. A.; McNamara, K.; Cohen, T. J. Org. Chem. 1992, 57,

1968e1969.84. Cohen, T.; McNamara, K.; Kuzmenko, M. A.; Ramig, K.; Landi, J. J., Jr.; Dong, Y.

Tetrahedron 1993, 49, 7931e7942.

http://refhub.elsevier.com/S0040-4020(14)00978-8/sref1























































































































































































































85. Piers, E.; Renaud, J. J. Chem. Soc., Chem. Commun. 1990, 1324e1326.86. Ihara, M.; Suzuki, T.; Katogi, M.; Taniguchi, N.; Fukumoto, K. J. Chem. Soc.,

Perkin Trans. 1 1992, 865e873.87. Ihara, M.; Suzuki, T.; Katogi, M.; Taniguchi, N.; Fukumoto, K. J. Chem. Soc.,

Chem. Commun. 1991, 646e647.88. Foley, D. A.; O’Leary, P.; Buckley, N. R.; Lawrence, S. E.; Maguire, A. R. Tetra-

hedron 2013, 69, 1778e1794.89. Kuwahara, S.; Shibata, Y.; Hiramatsu, A. Liebigs Ann. Chem. 1992, 993e995.90. Wakamatsu, T.; Akasaka, K.; Ban, Y. J. Org. Chem. 1979, 44, 2008e2012.91. Ayer, W. A.; Browne, L. M.; Fung, S. Can. J. Chem. 1976, 54, 3276e3282.92. Nemoto, H.; Nagai, M.; Fukumoto, K. Tetrahedron 1985, 41, 2361e2368.93. Peters, J. A. M.; Posthumus, T. A. P.; Vliet, N. P.; Zeelen, F. J.; Johnson, W. S. J.

Org. Chem. 1980, 45, 2208e2214.94. Mori, K.; Koga, Y. Bioorg. Med. Chem. Lett. 1992, 2, 391e394.95. Blay, G.; Cardona, L.; Garcia, B.; Pedro, J. R. J. Org. Chem. 1993, 58, 7204e7208.96. Segal, R.; Eden, L.; Danin, A.; Kaiser, M.; Duddeck, H. Phytochemistry 1984, 23,

2954e2956.97. Srikrishna, A.; Ravi, G.; Satyanarayana, G. Tetrahedron Lett. 2006, 48, 73e76.98. Canet, J.-L.; Fadel, A.; Salun, J. J. Org. Chem. 1992, 57, 3463e3473.99. Dauben, W. G.; Kessel, C. R.; Takemura, K. H. J. Am. Chem. Soc. 1980, 102,

6893e6894.100. Kametani, T.; Yukawa, H.; Honda, T. J. Chem. Soc., Chem. Commun. 1988,

685e687.101. Ishibashi, H.; Uemura, N.; Nakatani, H.; Okazaki, M.; Sato, T.; Nakamura, N.;

Ikeda, M. J. Org. Chem. 1993, 58, 2360e2368.102. Kodama, M.; Takahashi, T.; Kojima, T.; Ito, S. Tetrahedron 1988, 44, 7055e7062.103. Li, Y.; Yue, X.; Xing, Y. Tetrahedron Lett. 1993, 34, 2799e2800.104. Grigorieva, N. Y.; Moiseenkov, A. M. Synthesis 1989, 591e595.105. Ireland, R. E.; Anderson, R. C.; Badoud, R.; Fitzsimmons, B. J.; McGarvey, G. J.;

Thaisrivongs, T.; Wilcox, C. S. J. Am. Chem. Soc. 1983, 105, 1988e2006.106. Willis, M. C.; Randell-Sly, H. E.; Woodward, R. L.; Currie, G. S. Org. Lett. 2005, 7,

2249e2251.107. Ohshima, T.; Xu, Y.; Takita, R.; Shimizu, S.; Zhong, D.; Shibasaki, M. J. Am. Chem.

Soc. 2002, 124, 14546e14547.108. Ohshima, T.; Xu, Y.; Takita, R.; Shibasaki, M. Tetrahedron 2004, 60, 9569e9588.109. Knapp, S.; Trope, A. F.; Theodore, M. S.; Hirata, N.; Barchi, J. J. J. Org. Chem.

1984, 49, 608e614.110. Schreiber, S. L.; Kelly, S. E.; Porco, J. A.; Sammakia, T.; Suh, E. M. J. Am. Chem.

Soc. 1988, 110, 6210e6218.111. Stotter, P. L.; Hornish, R. E. J. Am. Chem. Soc. 1973, 95, 4444e4446.112. Fujisawa, T.; Mobele, B. I.; Shimizu, M. Tetrahedron Lett. 1992, 33, 5567e5570.113. Fechter, M. H.; Gruber, K.; Avi, M.; Skranc, W.; Schuster, C.; P€ochlauer, P.;

Klepp, K. O.; Griengl, H. Chem.dEur. J. 2007, 13, 3369e3376.114. Hegemann, K.; Fr€ohlich, R.; Haufe, G. Eur. J. Org. Chem. 2004, 2181e2192.115. Ward, D. E. Chem. Commun. 2011, 11375e11393.116. Ward, D. E.; Jheengut, V.; Beye, G. E. J. Org. Chem. 2006, 71, 8989e8992.117. Beye, G. E.; Ward, D. E. J. Am. Chem. Soc. 2010, 132, 7210e7215.118. Ward, D. E.; Jheengut, V.; Akinnusi, O. T. Org. Lett. 2005, 7, 1181e1184.119. Kawasaki, T.; Tanaka, H.; Tsutsumi, T.; Kasahara, T.; Sato, I.; Soai, K. J. Am. Chem.

Soc. 2006, 128, 6032e6033.120. Schellhaas, K.; Schmalz, H.-G.; Bats, J. W. Chem.dEur. J. 1998, 4, 57e66.121. Ireland, R. E.; Marshall, J. A. J. Org. Chem. 1962, 27, 1615e1619.122. Paterson, I.; Fleming, I. Tetrahedron Lett. 1979, 11, 995e998.123. Kita, Y.; Segawa, J.; Haruta, J.-i.; Yasuda, H.; Tamura, Y. J. Chem. Soc., Perkin

Trans. 1 1982, 1099e1104.124. Narjes, F.; Schaumann, E. Liebigs Ann. Chem. 1993, 841e846.125. Nicolaou, K. C.; Hummel, C. W.; Bockovich, N. J.; Wong, C.-H. J. Chem. Soc.,

Chem. Commun. 1991, 870e872.126. Sebesta, D. P.; Roush, W. R. J. Org. Chem. 1992, 57, 4799e4802.127. Nakayama, J.; Yamaoka, S.; Hoshino, M. Tetrahedron Lett. 1987, 28, 1799e1802.128. Larsson, M.; Galandrin, E.; H€ogberg, H.-E. Tetrahedron 2004, 60, 10659e10669.129. Mikami, K.; Yajima, T.; Siree, N.; Terada, M.; Suzuki, Y.; Kobayashi, I. Synlett

1996, 837e838.

130. Mikami, K.; Yajima, T.; Siree, N.; Terada, M.; Suzuki, Y.; Takanishi, Y.; Takezoe,H. Synlett 1999, 1895e1898.

131. Autrey, R. L.; Scullard, P. W. J. Am. Chem. Soc. 1968, 90, 4917e4923.132. Nishimura, K.; Ono, M.; Nagaoka, Y.; Tomioka, K. Angew. Chem., Int. Ed. 2001,

40, 440e442.133. Rana, N. K.; Singh, V. K. Org. Lett. 2011, 13, 6520e6523.134. Nishide, K.; Shigeta, Y.; Obata, K.; Node, M. J. Am. Chem. Soc. 1996, 118,

13103e13104.135. Boger, D. L.; Menezes, R. F.; Honda, T. Angew. Chem., Int. Ed. Engl. 1993, 32,

273e275.136. Nagao, Y.; Dai, W.-M.; Ochiai, M.; Shiro, M. Tetrahedron 1990, 46, 6361e6380.137. Corey, E. J.; Shimoji, K. J. Am. Chem. Soc. 1983, 105, 1662e1664.138. Kodama, M.; Kurihara, T.; Ito, S. Can. J. Chem. 1979, 57, 3343e3345.139. Crossley, N. S.; Djerassi, C.; Kielczewski, M. A. J. Chem. Soc. 1965, 6253e6264.140. Masjedizadeh, M. R.; Pames, H. J. Label. Comp. Radiopharm. 1995, 38, 41e51.141. Nemoto, H.; Ishibashi, H.; Nagamochi, M.; Fukumoto, K. J. Org. Chem. 1992, 57,

1707e1712.142. Ling, T.; Xiang, A. X.; Theodorakis, E. A. Angew. Chem., Int. Ed. 1999, 38,

3089e3091.143. Li, F.; Calabrese, D.; Brichacek, M.; Lin, I.; Njardarson, J. T. Angew. Chem., Int. Ed.

2012, 51, 1938e1941.144. Kropf, J. E.; Meigh, I. C.; Bebbington, M. W. P.; Weinreb, S. M. J. Org. Chem.

2006, 71, 2046e2055.145. Harring, S. R.; Livinghouse, T. Tetrahedron Lett. 1989, 30, 1499e1502.146. Urrutia, A.; Rodriguez, J. G. Tetrahedron 1999, 55, 11095e11108.147. Rehnberg, N.; Magnusson, G. J. Org. Chem. 1990, 55, 4340e4349.148. Rao, H. S. P.; Geetha, K.; Kamalraj, M. RSC Adv. 2011, 1, 1050e1059.149. Saito, T.; Fujii, H.; Hayashibe, S.; Matsushita, T.; Kato, H.; Kobayashi, K. J. Chem.

Soc., Perkin Trans. 1 1996, 1897e1903.150. Kennedy, M.; McKervey, M. A. J. Chem. Soc., Perkin Trans. 1 1991, 2565e2574.151. Natsugari, H.; Matsushita, Y.; Tamura, N.; Yoshioka, K.; Ochiai, M. J. Chem. Soc.,

Perkin Trans. 1 1983, 403e411.152. Chowdhury, G.; Cho, S.-H.; Pegg, A. E.; Guengerich, F. P. Angew. Chem., Int. Ed.

2013, 52, 12879e12882.153. Dawson, P. E.; Muir, T. W.; Clark-Lewis, I.; Kent, S. B. H. Science 1994, 266,

776e779.154. Perlstein, M. T.; Atassi, M. Z.; Cheng, S. H. Biochem. Biophys. Acta 1971, 236,

174e182.155. Yan, L. Z.; Dawson, P. E. J. Am. Chem. Soc. 2001, 123, 526e533.156. Arsequell, G.; Gonzalez, A.; Valencia, G. Tetrahedron Lett. 2001, 42, 2685e2687.157. Hoffmann, F. W.; Ess, R. J.; Simmons, T. C.; Hanzel, R. S. J. Am. Chem. Soc. 1956,

78 6414e6414.158. Walling, C.; Rabinowitz, R. J. Am. Chem. Soc. 1957, 79 5326e5326.159. Walling, C.; Basedow, O. H.; Savas, E. S. J. Am. Chem. Soc. 1960, 82, 2181e2184.160. Chen, J.; Wan, Q.; Yuan, Y.; Thu, J.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2007,

46, 9248e9252.161. Wilson, R. M.; Dong, S.; Wang, P.; Danishefsky, S. J. Angew. Chem. 2013, 52,

7646e7665.162. Dawson, P. E. Isr. J. Chem. 2011, 51, 862e867.163. Rohde, H.; Seitz, O. Biopolymers (Pept. Sci.) 2010, 94, 551e559.164. Haase, C.; Rohde, H.; Seitz, O. Angew. Chem., Int. Ed. 2008, 47, 6807e6810.165. Chen, J.; Wan, Q.; Yuan, Y.; Thu, J.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2008,

47, 8521e8524.166. Shang, S.; Tan, Z.; Dong, S.; Danishefsky, S. J. J. Am. Chem. Soc. 2011, 133,

10784e10786.167. Crich, D.; Banerjee, A. J. Am. Chem. Soc. 2007, 129, 10064e10065.168. Yang, R.; Pasunooti, K. K.; Li, F.; Liu, X.-W.; Liu, C.-F. J. Am. Chem. Soc. 2009, 131,

13592e13593.169. Thompson, R. E.; Chan, B.; Radom, L.; Jolliffe, K. A.; Payne, R. J. Angew. Chem.,

Int. Ed. 2013, 52, 9723e9727.170. Wang, L.; He, W.; Yu, Z. Chem. Soc. Rev. 2013, 42, 599e621.
























































































































































































































dron 70 (2014) 8983e9027 9027
J. Rentner et al. / Tetrahe
Biographical sketch

Jana Rentner was born in Halle/Saale (Germany) in 1983. In 2007 she finished hermaster thesis in chemistry at the University of Leipzig (Germany) in Organic Synthesisin the group of Prof. Rolf Breinbauer. In 2008 she followed Rolf to Graz University ofTechnology (Austria) where she received her PhD in 2012. After brief post-doctoralwork in 2012 in the group of Dr. Mandana Gruber in Graz (Austria), she accepted a po-sition in pharmaceutical development in industry.

Marko Kljajic was born in Derventa (Bosnia and Herzegovina) in 1988. After finishinghis BSc in Chemistry, he continued his Master studies at the Graz University of Tech-nology in Graz (Austria). He finished his MSc thesis on the topic of Pd-catalyzed ally-lations of phenols under the guidance of Prof. Rolf Breinbauer. At the moment he isworking on the synthesis of covalent binding inhibitors for activity-based proteomics.

Lisa Offner was born in Leoben (Austria) in 1989. In 2008 she started studying chem-istry at the Graz University of Technology where she received her MSc degree beingmentored by Dr. Mandana Gruber and Prof. Rolf Breinbauer at the Institute of OrganicChemistry. Currently she is studying the Master’s program in Biotechnology at the GrazUniversity of Technology, starting her master thesis in the field of synthetic biology inDr. Birgit Wiltschi’s group.

Rolf Breinbauer was born in Sch€arding (Austria) in 1970. He studied chemistry at theVienna University of Technology and the University of Heidelberg and received his PhDunder the guidance of Prof. Manfred T. Reetz at the Max-Planck-Institut f€ur Kohlenfor-schung in M€ulheim/Ruhr (Germany) in 1998. After working as a Post-Doc with an Er-win-Schr€odinger-Fellowship in the laboratory of Prof. Eric N. Jacobsen (HarvardUniversity), he moved in 2000 to Dortmund (Germany) as a group leader at theMax-Planck-Institute of Molecular Physiology (Department Head: Prof. Herbert Wald-mann) and as a Junior Professor at the University of Dortmund. From 2005 to 2007 hewas a Professor of Organic Chemistry at the University of Leipzig. Since 2007 he is FullProfessor of Organic Chemistry at the Graz University of Technology in Graz (Austria).The research focus of his group is the design and synthesis of molecular probes forChemical Biology and the development of new synthetic methods.

Documents

Recent advances and applications of reductive desulfurization